Multidrug resistance (MDR) is the term used to describe the resistance of cancer cells to chemotherapy, a resistance which can occur intrinsically or which can be acquired following a course of chemotherapy treatment. Acquired MDR occurs when tumor cells that survive initial chemotherapy are found to possess increased resistance to both the original therapeutic drug and other unrelated drugs.
Studies of acquired MDR have shown that the resistance is correlated with increased expression of cell surface glycoproteins known as P-glycoprotein and/or multidrug resistance related protein (MRP). It is believed that the mechanism of MDR involves decreased accumulation of anticancer drugs in cells due to energy-dependent transport of the drugs out of the cancer cells, which is mediated by P-glycoprotein or MRP.
Reversing agents or chemosensitizers have been discovered which reverse MDR by competing for the transport systems which are responsible for resistance. The reversing agents compete for drug binding to P-glycoprotein and/or MRP, thus effecting increased cellular accumulation of anticancer agents. Agents that reverse MDR include certain calcium channel blockers, calmodulin antagonists, alkaloid analogs, steroids and hormonal analogs, some hydrophobic cationic compounds and cyclosporins.
For example, verapamil, a calcium channel blocker, is a potent and effective reversing agent in cultured cells. Verapamil has been shown to sensitize MDR cells to anticancer drugs, promote intracellular accumulation of those drugs and compete for binding to P-glycoprotein (Tsuruo et al., Cancer Res. 41:1967 (1981)). A serious impediment to the use of verapamil and other calcium-channel blockers is the potentially life-threatening cardiovascular effects in humans at the doses required to reverse MDR (U. DeFaire and T. Lundman, J. Cardiol. 6:195 (1977); Candell et al., Chest 75:200 (1979)).
Because of their demonstrated effectiveness in attenuating drug resistance in tumor cells, the development of MDR reversing agents in anticancer chemotherapy continues to be an area of active investigation. However, a need exists for new reversing and/or chemosensitizing agents which enable treatment of drug resistant cells, so as to allow intracellular accumulation of anticancer drugs with less systemic toxicity, thereby overcoming the above-noted drawbacks attendant the use of the MDR reversing agents reported to date.